chr16-89758599-C-G

Position:

• chr16-89758599-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000135.4(FANCA):​c.2959G>C​(p.Ala987Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.187

Genes affected

FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

FANCA (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4	c.2959G>C	p.Ala987Pro	missense_variant	30/43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.2959G>C	p.Ala987Pro	missense_variant	30/43		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.2959G>C	p.Ala987Pro	missense_variant	30/43	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251414 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461558 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 21, 2017	This sequence change replaces alanine with proline at codon 987 of the FANCA protein (p.Ala987Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the homozygote state in two siblings from a single family presenting with features consistent with Fanconi anemia (PMID: 21519011). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on FANCA function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Fanconi anemia complementation group A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Nov 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.68	T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.54
Sift	Benign	0.075	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.33	B;.
Vest4		0.39
MutPred		0.40		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.97
ClinPred		0.063	T
GERP RS		1.7
Varity_R		0.15
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752735858; hg19: chr16-89825007;